Despite the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), there is an absence of FDA-approved treatments for liver fibrosis and metabolic dysfunction-associated steatohepatitis (MASH). This therapeutic gap increases a patients’ risk of developing liver cancer and reduces life expectancy.
Single nucleotide polymorphisms (SNPs) play a significant role in dictating the onset and intensity of MASLD. Aimed at identifying novel SNPs implicated in MASLD pathogenesis, we assessed the susceptibility of eight genetically diverse mouse strains to western diet-induced MASH and liver fibrosis. Using quantitative trait loci (QTL) mapping, we identified SNPs in inositol phosphate 1 polyphosphatase (INPP1) as a signature of resistance to MASH and liver fibrosis.
INPP1 is a magnesium-dependent phosphatase involved in inositol phosphate metabolism, catalysing the hydrolysis of a phosphate group within the inositol ring of various inositol polyphosphates. However, little is known about the role of INPP1 in lipid metabolism and MASLD progression. Using single gRNA knockout in liver cells, we show that deletion of INPP1 leads to a substantial decrease in fatty acid uptake and de novo lipogenesis, an increase in fatty acid and glucose oxidation, and increased release of very-low-density lipoproteins, overall reducing lipid accumulation by 90%. Combined proteomics and lipidomics analysis confirm the reduced capacity for glucose and fatty acid metabolism, but not amino acid metabolism, in addition to substantial reductions in triacylglycerol, diacylglycerol, and cholesterol ester lipid species.
Together, this study identifies INPP1 as a novel regulator of hepatic lipid and glucose metabolism, and as a potential new therapeutic target for MASLD.
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